Renal xenobiotic transporters are differentially expressed in mice following cisplatin treatment

Area of Science:

• Nephrology
• Pharmacology
• Molecular Biology

Background:

• Cisplatin is a potent chemotherapy agent with known nephrotoxic effects.
• Kidney xenobiotic transporters play a crucial role in drug disposition and toxicity.
• Understanding transporter alterations during acute kidney injury (AKI) is vital for managing cisplatin toxicity.

Purpose of the Study:

• To investigate changes in mRNA and protein expression of renal xenobiotic transporters in response to cisplatin-induced AKI in mice.
• To elucidate the role of specific uptake and efflux transporters in the kidney's response to cisplatin nephrotoxicity.

Main Methods:

• Male C57BL/6J mice were administered a single dose of cisplatin (18 mg/kg) or vehicle.
• Kidney tissues were analyzed four days post-treatment for plasma BUN, histopathology, and transporter expression via mRNA and Western blot.
• Expression levels of organic anion transporters (Oat), cation transporters (Oct), Oatp, Mrp, Mdr, Bcrp, and Mate were assessed.

Main Results:

• Cisplatin induced renal proximal tubule necrosis, elevated plasma BUN, and increased kidney injury molecule-1 mRNA.
• Expression of efflux transporters (Mrp2, Mrp4, Mrp5, Mdr1a, Mdr1b) and uptake transporters (Oatp2a1, Oatp2b1) increased at mRNA and/or protein levels.
• Expression of uptake transporters (Oat1, Oat2, Oct2, Oatp1a1) decreased, while several other transporters remained unchanged.

Conclusions:

• Cisplatin-induced AKI leads to coordinated changes in renal xenobiotic uptake and efflux transporter expression.
• Enhanced expression of efflux transporters and specific uptake transporters suggests an adaptive mechanism to reduce intracellular chemical accumulation and enhance urinary clearance.
• Altered transporter expression may contribute to the nephrotoxic effects and disposition of cisplatin and other xenobiotics during kidney injury.